ABSTRACT: Cigarette smoking is the primary risk factor for lung cancer and there are gender differences in the relationship between smoking and this disease. The contributions of genetic risk factors and tobacco exposure to lung cancer development have been studied. Furthermore combined effect of genetic polymorphisms in CYP1A1 and GSTM1 (phase I and II enzymes that metabolize tobacco carcinogens) is reported to be associated with a higher risk of lung cancer among women than men (OR = 6.54 vs. 2.36). Lung cancer can develop among about 10% of subjects with no prior history of cigarette smoking. Therefore, risk factors other than cigarette smoking may attribute to the development of some lung tumors. Human Papillomavirus (HPV) causes cervical cancer in women and is associated with most other anogenital cancers as well as oropharngeal cancers in both men and women. Some studies have suggested that HPV may be associated with a subset of lung tumors, although an etiologic link has not been firmly established. We and others have suggested that HPV may play a role in the development of second primary lung cancers in women who had a first diagnosis of cervical cancer. It is not yet clear, whether HPV may contribute to the gender differences in lung cancer development. However further investigation of the role of HPV in lung cancer among women is warranted. Gene-viral interactions in lung cancer have not been studied. However, one In vitro study reports that GSTM1 expression is lower in cells that express the HPV oncoproteins. If HPV is associated with lung cancer development, it is possible that this virus will play an additional role in the subject's ability to handle tobacco carcinogenesis since expression of the GSTM1 protein helps to prevent the damaging effects of tobacco carcinogens through their detoxification. We hypothesize that gender differences in lung cancer may be associated with HPV infection. We propose to first perform a pooled analysis of cross-sectional studies to study the association of HPV in lung tumors and second, perform a cross-sectional study to investigate the relationships of HPV, GSTM1 and CYP1A1 polymorphisms in male and female lung cancer patients. There are no studies that have investigated gene-viral-environment relationships in lung cancer. The goal of this study is to evaluate the prevalence of HPV among lung cancer cases and to explore the possible gene-viral interactions in this disease. Our long term goal is to better understanding of gender-specific differences in lung cancer development. We expect that these proposed studies will help to shape our investigation of gender differences in lung cancer.